Nicole Cristell

High-Sensitivity C-Reactive Protein Is Within Normal Levels at the Very Onset of First ST-Segment Elevation Acute Myocardial Infarction in 41% of Cases: A Multiethnic Case-Control Study

OBJECTIVES This study sought to assess the prevalence of normal levels of high sensitivity C-reactive protein (hsCRP) at the very onset of ST-segment elevation myocardial infarction (STEMI). BACKGROUND Levels of hsCRP ≥2 mg/l identify individuals who benefit from lipid lowering and possibly anti-inflammatory agents, but how many patients develop infarction in spite of hsCRP levels <2 mg/l and thus would be ineligible for these treatments? METHODS We studied 887 patients with unequivocally documented STEMI as the first manifestation of coronary disease and 887 matched control subjects from urban areas of Italy, Scotland, and China. Blood samples were obtained before reperfusion strategies <6 h from symptoms onset in order to limit acute event-related increases. RESULTS hsCRP values were similar in samples obtained <2 h, 2 to 4 h, and 4 to 6 h from symptoms onset in all ethnic groups, consistent with the delayed hsCRP elevation after myocardial necrosis and thus indicative of pre-infarction levels. Median hsCRP values were significantly higher in patients than in control subjects: 2.49 (interquartile range [IQR]: 1.18 to 5.55) mg/l versus 1.32 (IQR: 0.58 to 3.10) mg/l (p < 0.0001), which is consistent with previous findings. However, 41% of patients had hsCRP levels <2 mg/l and conversely, 37% of control subjects had values ≥2 mg/l. CONCLUSIONS The measurement of hsCRP, with a 2 mg/l cutoff, would not have predicted 41% of unequivocally documented STEMIs in 3 ethnic groups without evidence of previous coronary disease, thus indicating both its limitations as an individual prognostic marker and as an indicator of a generalized inflammatory pathogenetic component of STEMI. New specific prognostic and therapeutic approaches should be found for such a large fraction of patients at risk.

Identification and Predictive Value of Interleukin-6+ Interleukin-10+ and Interleukin-6− Interleukin-10+ Cytokine Patterns in ST-Elevation Acute Myocardial Infarction

Rationale: At the onset of ST-elevation acute myocardial infarction (STEMI), patients can present with very high circulating interleukin-6 (IL-6+) levels or very low-IL-6– levels. Objective: We compared these 2 groups of patients to understand whether it is possible to define specific STEMI phenotypes associated with outcome based on the cytokine response. Methods and Results: We compared 109 patients with STEMI in the top IL-6 level (median, 15.6 pg/mL; IL-6+ STEMI) with 96 in the bottom IL-6 level (median, 1.7 pg/mL; IL-6− STEMI) and 103 matched controls extracted from the multiethnic First Acute Myocardial Infarction study. We found minimal clinical differences between IL-6+ STEMI and IL-6− STEMI. We assessed the inflammatory profiles of the 2 STEMI groups and the controls by measuring 18 cytokines in blood samples. We exploited clustering analysis algorithms to infer the functional modules of interacting cytokines. IL-6+ STEMI patients were characterized by the activation of 2 modules of interacting signals comprising IL-10, IL-8, macrophage inflammatory protein-1&agr;, and C-reactive protein, and monocyte chemoattractant protein-1, macrophage inflammatory protein-1&bgr;, and monokine induced by interferon-&ggr;. IL-10 was increased both in IL-6+ STEMI and IL-6− STEMI patients compared with controls. IL-6+IL-10+ STEMI patients had an increased risk of systolic dysfunction at discharge and an increased risk of death at 6 months in comparison with IL-6−IL-10+ STEMI patients. We combined IL-10 and monokine induced by interferon-&ggr; (derived from the 2 identified cytokine modules) with IL-6 in a formula yielding a risk index that outperformed any single cytokine in the prediction of systolic dysfunction and death. Conclusions: We have identified a characteristic circulating inflammatory cytokine pattern in STEMI patients, which is not related to the extent of myocardial damage. The simultaneous elevation of IL-6 and IL-10 levels distinguishes STEMI patients with worse clinical outcomes from other STEMI patients. These observations could have potential implications for risk-oriented patient stratification and immune-modulating therapies.

Identification and Predictive Value of IL6(+)IL10(+) and IL6(-)IL10(+) Cytokine Patterns in ST-Elevation Acute Myocardial Infarction

Rationale: At the onset of ST-elevation acute myocardial infarction (STEMI), patients can present with very high circulating interleukin-6 (IL-6+) levels or very low-IL-6– levels. Objective: We compared these 2 groups of patients to understand whether it is possible to define specific STEMI phenotypes associated with outcome based on the cytokine response. Methods and Results: We compared 109 patients with STEMI in the top IL-6 level (median, 15.6 pg/mL; IL-6+ STEMI) with 96 in the bottom IL-6 level (median, 1.7 pg/mL; IL-6− STEMI) and 103 matched controls extracted from the multiethnic First Acute Myocardial Infarction study. We found minimal clinical differences between IL-6+ STEMI and IL-6− STEMI. We assessed the inflammatory profiles of the 2 STEMI groups and the controls by measuring 18 cytokines in blood samples. We exploited clustering analysis algorithms to infer the functional modules of interacting cytokines. IL-6+ STEMI patients were characterized by the activation of 2 modules of interacting signals comprising IL-10, IL-8, macrophage inflammatory protein-1&agr;, and C-reactive protein, and monocyte chemoattractant protein-1, macrophage inflammatory protein-1&bgr;, and monokine induced by interferon-&ggr;. IL-10 was increased both in IL-6+ STEMI and IL-6− STEMI patients compared with controls. IL-6+IL-10+ STEMI patients had an increased risk of systolic dysfunction at discharge and an increased risk of death at 6 months in comparison with IL-6−IL-10+ STEMI patients. We combined IL-10 and monokine induced by interferon-&ggr; (derived from the 2 identified cytokine modules) with IL-6 in a formula yielding a risk index that outperformed any single cytokine in the prediction of systolic dysfunction and death. Conclusions: We have identified a characteristic circulating inflammatory cytokine pattern in STEMI patients, which is not related to the extent of myocardial damage. The simultaneous elevation of IL-6 and IL-10 levels distinguishes STEMI patients with worse clinical outcomes from other STEMI patients. These observations could have potential implications for risk-oriented patient stratification and immune-modulating therapies.

Questing for circadian dependence in ST-segment-elevation acute myocardial infarction: A multicentric and multiethnic study

Rationale: Four monocentric studies reported that circadian rhythms can affect left ventricular infarct size after ST-segment–elevation acute myocardial infarction (STEMI). Objective: To further validate the circadian dependence of infarct size after STEMI in a multicentric and multiethnic population. Methods and Results: We analyzed a prospective cohort of subjects with first STEMI from the First Acute Myocardial Infarction study that enrolled 1099 patients (ischemic time <6 hours) in Italy, Scotland, and China. We confirmed a circadian variation of STEMI incidence with an increased morning incidence (from 6:00 am till noon). We investigated the presence of circadian dependence of infarct size plotting the peak creatine kinase against time onset of ischemia. In addition, we studied the patients from the 3 countries separately, including 624 Italians; all patients were treated with percutaneous coronary intervention. We adopted several levels of analysis with different inclusion criteria consistent with previous studies. In all the analyses, we did not find a clear-cut circadian dependence of infarct size after STEMI. Conclusions: Although the circadian dependence of infarct size supported by previous studies poses an intriguing hypothesis, we were unable to converge toward their conclusions in a multicentric and multiethnic setting. Parameters that vary as a function of latitude could potentially obscure the circadian variations observed in monocentric studies. We believe that, to assess whether circadian rhythms can affect the infarct size, future study design should not only include larger samples but also aim to untangle the molecular time–dynamic mechanisms underlying such a relation.

Molecular study of human herpesvirus 6 and 8 involvement in coronary atherosclerosis and coronary instability

Several lines of evidence suggest the involvement of infectious agents in the pathogenesis of atherosclerosis. Furthermore, a correlation between infection‐driven inflammatory burden and acute manifestation of coronary artery disease has been hypothesized. The aim of this work was to assess whether human herpesvirus (HHV)‐6 and HHV‐8, two DNA viruses with a distinct tropism for endothelium and lymphocytes, may be associated with coronary instability. An age‐ and gender‐matched cross‐sectional study was undertaken in 70 patients with testing of plasma HHV‐6 and HHV‐8 DNA load in different cardiovascular clinical settings: 29 patients with acute myocardial infarction, 21 patients with stable coronary artery disease, and 20 patients without coronary and carotid artery atherosclerosis subjected to cardiac valve replacement. In all patients, HHV‐6 and HHV‐8 plasma DNA was tested by using highly sensitive, calibrated quantitative real‐time PCR assays which employ a synthetic DNA calibrator to adjust for DNA extraction and amplification efficiency. HHV‐8 viremia was undetectable in all three groups. HHV‐6 viremia was detected in a substantial fraction of the samples examined (18.6%) without significant differences among the three groups (ST segment elevation myocardial infarction: 17.2%; stable coronary artery disease: 14.3%; patients without coronary and carotid artery atherosclerosis: 25%). Furthermore, no significant differences in plasma HHV‐6 load were observed amongst the three groups of patients. These findings indicate that coronary instability is not associated specifically with active HHV‐6 or HHV‐8 infection. However, an unusually high rate of active HHV‐6 infection was documented among patients without atherosclerosis admitted to hospital with cardiac disease. J. Med. Virol. 84:1961–1966, 2012.

Serum uric acid on admission predicts in-hospital mortality in patients with acute coronary syndrome

BACKGROUND Despite the association between uric acid and cardiovascular disease has been known for decades, the prognostic value of serum uric acid (UA) in all clinical manifestations of acute coronary syndrome (ACS), namely ST-elevation myocardial infarction (STEMI), NSTEMI and unstable angina, has not been definitively assessed. METHODS This retrospective analysis included patients from previous SPAI and FAMI studies with the aim to investigate the association between serum uric acid and major adverse cardiovascular events at 180days from hospital admission. RESULTS 1548 patients were considered and divided in four groups, according UA concentration. Uricemia was significantly associated with gender, BMI, arterial hypertension, HDL-cholesterol, triglycerides, metabolic syndrome and glomerular filtration rate in univariate analysis. Multivariate logistic regression indicated that UA >6.0mg/dL on admission increased the risk of in-hospital mortality in overall population (OR 2.9, 95%CI 1.4-6.1; p=0.0057) and in patients with de novo ACS (OR 3.2, 95%CI 1.5-6.8; p=0.0033). Comparable results were also obtained after adjusting the model for age, gender, body mass index, glomerular filtration rate, metabolic syndrome, acute revascularization and ethnicity. A positive correlation was observed between UA and C reactive protein concentrations in in-hospital deaths only (rho 0.41, p=0.027). CONCLUSION In patients with acute coronary syndrome, uricemia levels above the current international reference limit (6.0mg/dl) were associated with in-hospital mortality, independently from ethnicity and renal function.

The predictive role of renal function and systemic inflammation on the onset of de novo atrial fibrillation after cardiac surgery

Background The association between postoperative atrial fibrillation (POAF) and renal function was previously grounded in patients undergoing coronary artery bypass grafting through unknown mechanisms. We aim to investigate the association between renal function and POAF in a cohort composed mostly of patients undergoing valve surgery and to explore the role of inflammation as a pathogenic mechanism linking renal dysfunction and arrhythmogenesis. Methods Altogether 444 patients who underwent cardiac surgery without previous history of atrial fibrillation were analysed. Serum creatinine and high sensitivity C-reactive protein (hs-CRP) concentrations were obtained at baseline and on the 3rd, 8th and 15th postoperative day; estimated glomerular filtration rate (eGFR) was calculated by the Modified Diet Renal Disease (MDRD) formula. Patients were divided into three groups on the basis of baseline eGFR. Results Overall, 173 (39%) patients developed POAF, 29.5% in the group with normal eGFR (≥90 ml/min/1.73 m2), 43.3% among patients with eGFR 60–90 ml/min/1.73 m2 and 55.6% in the group with eGFR ≤60 ml/min/1.73 m2. Patients developing POAF had lower eGFR on all the samples. At baseline preoperatively hs-CRP levels did not differ in the two groups. On multivariate analysis, age and eGFR were identified as independent predictors of POAF. The risk of POAF progressively increased from mild impairment (odds ratio (OR) 1.59, 95% confidence interval (CI) 1.01–2.50) to severe reduction of renal function (OR 2.35, 95% CI 1.25–4.48). Conclusions Age and eGFR were identified as the strongest predictors of POAF in a population largely composed of valve surgery patients. Renal function, even from early stage, is independently associated with the increasing risk of developing POAF.

PHARMACOGENOMIC IMPLICATIONS OF RENIN ANGIOTENSIN ALDOSTERONE SYSTEM INHIBITION IN ST-ELEVATION MYOCARDIAL INFARCTION

Background: A complex network of gene-environment interactions may be related to myocardial infarction. To date, several single nucleotide polymorphisms (SNPs) have been investigated as potential determinants in terms of predisposition, prognosis and response to therapy, but with no definite

AN EFFECTIVE MHEALTH SERVICE TO REDUCE BLOOD PRESSURE WITHOUT ADDING MEDICATIONS THROUGH PERSONALIZED AUTOMATED LIFESTYLE INTERVENTIONS

Current guidelines require prescription of lifestyle modifications for all patients with prehypertension and hypertension. Lifestyle counselling is often provided with general rules but to be effective it requires a strong commitment of health professionals. We evaluated the effect on blood

Applicability of the 2013 ACC/AHA Risk Assessment and Cholesterol Treatment Guidelines in the real world: results from a multiethnic case-control study

Abstract Background: The 2013 ACC/AHA cholesterol treatment guidelines have introduced a new cardiovascular risk assessment approach (PCE) and have revisited the threshold for prescribing statins. This study aims to compare the ex ante application of the ACC/AHA and the ATP-III guideline models by using a multiethnic case-control study. Methods: ATP-III-FRS and PCE were assessed in 739 patients with first STEMI and 739 age- and gender-matched controls; the proportion of cases and controls that would have been eligible for statin as primary prevention therapy and the discriminatory ability of both models were evaluated. Results: The application of the ACC/AHA compared to the ATP-III model, resulted in an increase in sensitivity [94% (95%CI: 91%–95%) vs. 65% (61%–68%), p< 0.0001], a reduction in specificity [19% (15%–22%) vs. 55% (51%–59%), p< 0.0001] with similar global accuracy [0.56 (0.53–0.59) vs.0.59 (0.57–0.63), p ns]. When stratifying for ethnicity, the accuracy of the ACC/AHA model was higher in Europeans than in Chinese (p = 0.003) and to identified premature STEMI patients within Europeans much better compared to the ATP-III model (p = 0.0289). Conclusion: The application of the ACC/AHA model resulted in a significant reduction of first STEMI patients who would have escaped from preventive treatment. Age and ethnicity affected the accuracy of the ACC/AHA model improving the identification of premature STEMI among Europeans only. Key messages According to the ATP-III guideline model, about one-third of patients with STEMI would not be eligible for primary preventive treatment before STEMI. The application of the new ACC/AHA cholesterol treatment guideline model leads to a significant reduction of the percentage of patients with STEMI who would have been considered at lower risk before the STEMI. The global accuracy of the new ACC/AHA model is higher in the Europeans than in the Chinese and, moreover, among the Europeans, the application of the new ACC/AHA guideline model also improved identification of premature STEMI patients.